The primary focus of our research continues to be the synthesis and study of complex molecules with proven or potential anti-cancer activity. Efficient laboratory synthetic routes are developed that provide access to new materials with potentially improved properties for study and biological evaluation. The elucidation of the detailed chemical processes that underlie the biological (antiproliferative) activity of the agents we study is a principal goal of our research. Specific synthetic targets include the natural antiproliferative agents avrainvillamide, stephacidin B, salinosporamides, quinocarcin, N1999A2, kedarcidin chromophore, and maduropeptin chromophore. In addition, we will execute a solid-phase split-pool synthesis of a library of ~1,000 saframycin analogs, a small library (-200compounds) of molecules bearing the 3-alkylidene3-H- indole-1-oxide function, a novel class of potential enzyme (protease) inhibitors, and a number of structural analogs of quinocarcin, avrainvillamide, and stephacidin B. We will synthesize a large number of analogs of the natural proteasomal inhibitor and antiproliferative agent salinosporamide. By design, the synthetic route under development incorporates three sites of structural variability; the route is also notably short and efficient. A major effort is underway in our laboratory to elucidate the molecular target(s) of the saframycins and, separately, the new class of natural antiproliferative agents represented by avrainvillamide and stephacidin B. We will continue to pursue studies designed to elucidate the details of the interaction of the protein target glyceraldehyde 3-phosphate dehydrogenase (GAPDH) with binary complexes of duplex DMA and saframycins, and the role this interaction may play in the antiproliferative activity of saframycins.